Our Drug Abuse Research Center continues its long-term thematic focus on The Dynamics of Signaling by Molecular Messengers Relevant to Actions of Drugs of Abuse. Multidisciplinary approaches are employed to enhance the conceptual synergy of the projects. Snyder will study novel molecular mechanisms of neurotoxicity that may mediate neurotoxic actions of drugs as well as neuroprotection with a focus upon (1) Nitric oxide (NO) influences upon COX2 and DexrasI-iron (2) Glyceraldehyde-3-phosphate dehydrogenase (3) Heme oxygenase/biliverdin reductase. Baraban will study (1) Tech, a neuronal RhoA GEF, and its actions on neuronal morphology and AMPA receptor trafficking as well as potential regulation by tyrosine phosphorylation (2) The Translin/Trax RNA binding complex, its binding partners and trafficking of candidate cargoes. The Dawsons will focus on NO in neuroprotection, addressing (1) How NO activates Ras (2) How Iduna is regulated by NMDA transmission/NO (3) Role of MEF2 in NO dependent survival (4) How the novel non-coring RNA NOIG17 is neuroprotective. Worley will investigate regulation by metabotropic glutamate receptors (mGluR) of protein synthesis, addressing (1) How mGluR-eEF2K/EF2 interactions regulate protein synthesis (2) How the cascade involving mGluR, Homer, PI3 kinase, Akt, tuberous sclerosis complex, Rheb (ras homolog enriched in brain), mTor, Dor (Deep Organe), and S6K/S6 is coupled to mGluR (3) Response to cocaine and opiates of animal models targeting EF2K, Rheb and Dor.